open access publication

Article, 2023

SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy

npj Genomic Medicine, ISSN 2056-7944, Volume 8, 1, Page 28, 10.1038/s41525-023-00370-z

Contributors

Roshandel, Delnaz 0000-0002-4902-8587 [1] Sanders, Eric J. [1] [2] Shakeshaft, Amy 0000-0003-1412-5413 [3] Panjwani, Naim 0000-0001-7551-0759 [1] Lin, Fan [1] Collingwood, Amber [3] Hall, Anna [3] Keenan, Katherine [1] Deneubourg, Celine 0000-0002-8854-6619 [3] Mirabella, Filippo [3] Topp, Simon [3] Zarubova, Jana [4] Thomas, Rhys Huw 0000-0003-2062-8623 [5] [6] Talvik, Inga [7] Syvertsen, Marte Roa 0000-0003-2182-4247 [8] Striano, Pasquale 0000-0002-6065-1476 [9] [10] Smith, Anna B. [3] Selmer, Kaja Kristine 0000-0003-4871-112X [11] Rubboli, Guido 0000-0002-5309-2514 [12] [13] Orsini, Alessandro [14] Ng, Ching Ching [15] Møller, Rikke Steensbjerre 0000-0002-9664-1448 [13] [16] Lim, Kheng-Seang 0000-0002-2787-2365 [15] Hamandi, Khalid 0000-0001-7116-262X [17] [18] Greenberg, David A. [19] Gesche, Joanna 0000-0002-0546-4619 [20] Gardella, Elena 0000-0002-7138-6022 [13] [16] Fong, Choong Yi [15] Beier, Christoph Patrick P 0000-0001-8268-1492 [20] Andrade, Danielle M. [2] [21] Jungbluth, Heinz 0000-0002-7159-3427 [3] [22] Richardson, Mark Philip 0000-0001-8925-3140 [3] [23] Pastore, Annalisa [3] Fanto, Manolis 0000-0001-7807-2563 [3] Pal, Deb K (Corresponding author) [3] [23] Strug, Lisa Joanna 0000-0003-0503-9740 (Corresponding author) [1] [2]

Affiliations

  1. [1] Hospital for Sick Children
    2. [NORA names: Canada; America, North; OECD];
  2. [2] University of Toronto
    3. [NORA names: Canada; America, North; OECD];
  3. [3] King's College London
    4. [NORA names: United Kingdom; Europe, Non-EU; OECD];
  4. [4] University Hospital in Motol
    5. [NORA names: Czechia; Europe, EU; OECD];
  5. [5] National Health Service England
    6. [NORA names: United Kingdom; Europe, Non-EU; OECD];

Abstract

Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and juvenile myoclonic epilepsy (JME). We performed a genome-wide association, colocalization, polygenic risk score, and pathway analysis of impulsivity in JME (n = 381). Results were followed up with functional characterisation using a drosophila model. We identified genome-wide associated SNPs at 8q13.3 (P = 7.5 × 10−9) and 10p11.21 (P = 3.6 × 10−8). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (P = 9.5 × 10−3). SLCO5A1 codes for an organic anion transporter and upregulates synapse assembly/organisation genes. Pathway analysis demonstrates 12.7-fold enrichment for presynaptic membrane assembly genes (P = 0.0005) and 14.3-fold enrichment for presynaptic organisation genes (P = 0.0005) including NLGN1 and PTPRD. RNAi knockdown of Oatp30B, the Drosophila polypeptide with the highest homology to SLCO5A1, causes over-reactive startling behaviour (P = 8.7 × 10−3) and increased seizure-like events (P = 6.8 × 10−7). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME (P = 1.60 × 10−3). SLCO5A1 loss-of-function represents an impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease.

Keywords

Drosophila, Drosophila model, Drosophila polypeptide, NLGN1, PTPRD, RNAi, RNAi knockdown, SLCO5A1, SNPs, aetiology, analysis, analysis of impulsivity, anion transport, assembly genes, association, attention-deficit hyperactivity disorder, behavior, bipolar disorder, cerebral cortex, characterisation, colocalization, cortex, disease, disorders, elevated impulsivity, enrichment, epilepsy, events, expression quantitative trait loci, functional characterisation, genes, genome-wide, genome-wide association, health, hyperactivity disorder, identified genome-wide, impulse, impulsivity scores, juvenile myoclonic epilepsy, loci, loss-of-function, mechanism, model, myoclonic epilepsy, organic anion transporter, pathway, pathway analysis, polygenic risk scores, polypeptide, quantitative trait loci, results, risk score, scores, seizure mechanisms, seizure-like events, seizures, startle behavior, trait loci, transport

Funders

  • Engineering and Physical Sciences Research Council
  • Ministry of Education, Universities and Research
  • National Institute for Health and Care Research
  • Epilepsy Research UK
  • The Research Council of Norway
  • Action Medical Research
  • Medical Research Council
  • Canadian Institutes of Health Research
  • Health and Care Research Wales
  • European Commission
  • Eisai (Japan)
  • Canada Research Chairs

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